: Papillomaviruses play a critical role in the development of several cancers of humans, especially in squamous cell carcinomas derived from genital, anal, oral, and epidermal sites. At least 95 percent of cervical carcinomas in women contain and express the papillomavirus genome. The current grant focuses on the most highly expressed gene in early papillomavirus lesions, E5. This gene encodes a small hydrophobic protein which inserts into Golgi and endoplasmic reticulum membranes and alters growth signaling pathways. The prototype E5 protein from bovine papillomavirus type I had long been known to activate the platelet-derived growth factor receptor. The mechanism for this activation appears to be due to its ability to bind to the receptor via its transmembrane domain and to "cross-link" receptors. TrAnsphosphorylation of the receptor and consequent downstream signaling are then presumed to result. However, we have recently discovered that the bovine papillomavirus E5 protein also binds a subunit of the Golgi V-ATPase proton pump, resulting in its inactivation and the consequent alkalinization of the Golgi lumen. Our goals are to determine whether the human papillomavirus E5 proteins exhibit the same activity. In addition, we plan to extend these studies to two other human tumor viruses, HTLV-1 and HHV-8, which encode E5-related proteins. Finally, our studies will examine whether the pleiotropic activities of E5 (especially those related to growth factor signaling, cell growth, and cell differentiation), might derive from its interaction with the V-ATPase. The ultimate goal is to examine the convergent activities of these hydrophobic, Golgi- tropic polypeptides6and their role in human neoplasia and virus biology.